Moderate to Severe Disease

Therapies that may be considered in patients with SB CD of

^Editor's Note: Some patients with ileitis did not respond to sulfasalazine.

moderate to severe activity or disease refractory to mesalamine therapy include corticosteroids, azathioprine (AZA) or 6-mercaptopurine(6-MP), methotrexate (MTX), and infliximab.

Corticosteroids

Conventional corticosteroids, both oral and parenteral forms, are effective for patients with moderate to severe flares. Doses equivalent to 40 to 60 mg/d (or 0.5 to 0.75 mg/kg/d) of prednisone are sufficient to induce remission; higher doses do not provide additional benefit and are not recommended. Parenteral corticosteroids should be initiated in patients with severe disease not responding to oral corticosteroids. Hospitalization along with a course of bowel rest is appropriate in these severely ill patients.

Budesonide

Newer corticosteroid preparations such as oral budesonide (Entercort) have the advantage of a greater topical anti-inflammatory action and a better toxicity profile than traditional corticosteroids. in patients with mild to moderate disease activity, budesonide at 9 mg/d is superior to placebo or mesalamine, and comparable to conventional steroids at equivalent of prednisolone 40 mg/d (Greenberg et al, 1994; Thomsen et al, 1998; Rutgeerts et al, 1994). The controlled-ileal release oral budesonide (Entocort) is formulated as Eudragit-L-coated microgranules with an internal ethylcellu-lose component that release budesonide at pH > 5.5. The primary site of release for budesonide (Entocort) is the ileocecal region. Thus, the most appropriate candidates for this agent are patients with ileal and/or right-sided colonic CD with mild to moderate disease severity. For induction of remission, oral budesonide is administered at 9 mg/d for 8 weeks. some individuals advocate tapering budesonide from 9 mg daily down to 6 mg/d for additional 1 to 2 weeks and then 3 mg daily for 1 to 2 further weeks and then discontinuing therapy.*

^Editor's Note: There are some who continue budesonide, 6 mg each morning along with mesalamine because the average remission on 6 mg/d was 7 months compared with 3 months on placebo. Calcium and vitamin D should be continued and bone density monitored.

AZA 6-MP

AZA or 6-MP is also effective as primary therapy in patients with moderately to severely active CD, regardless of disease distribution. The response rate of AZA or 6-MP therapy in controlled trials is approximately 54% (Sandborn, 1996). The delayed onset of action of up to 3 to 6 months limits its use as a single therapy in patients with severely active disease. Patients with moderate disease who are willing to tolerate active symptoms for that duration of time may be managed with AZA or 6-MP as single induction therapy. The effective dosages are generally considered to be 2.0 to 2.5 mg/kg/d for AZA and 1.0 to 1.5 mg/kg/d for 6-MP.More commonly AZA is combined with corticosteroids because corticosteroids act rapidly, and as they are being tapered the onset of action of AZA occurs. It remains controversial whether clinicians should routinely phenotype thiopurine methyltransferase (TPMT) enzyme before therapy initiation, or measure levels of active metabolites, 6-thioguanine nucleotides (6-TGN), while patients are on therapy (Cuffari et al, 1996; Dubinsky et al, 2000; Cuffari et al, 2001; Cuffari et al, 2004). If pretherapy determination of TPMT phenotype or genotype is not performed, the medication frequently is started at 50 mg/d, escalating by 25 mg every 4 to 8 weeks until reaching the target dose. Complete blood counts (CBCs) need to be monitored regardless of the status of TPMT enzyme. Similarly, liver-associated laboratory chemistries should be obtained periodically as well. Measuring erythrocyte 6-TGN levels is appropriate in patients not responding to therapy and in patients suspected of noncompliance. If metabolite levels are measured, the assay should be performed at least 2 to 3 weeks following any dose change. If metabolite levels are being followed dosage should be adjusted to achieve 6-TGN levels above 235 to 250 pmoles/8 x 108 erythrocytes.^

MTX is another immunomodulator used for the treatment of CD of moderate to severe activity, regardless of disease location. As an induction therapy, MTX is administered intramuscularly at 25 mg/week for 16 weeks (Feagan et al, 2000). MTX therapy has been shown in a clinical trial to result in complete steroid withdrawal and clinical remission in 39% of patients with active CD. The response rate was over 60% in an open label study. The onset of action is approximately 8 weeks. Similar to AZA and 6-MP, liver-associated laboratory chemistries and CBCs should be monitored every 2 to 4 weeks during induction therapy.

^Editor's Note: There is a separate chapter on AZA use in inflammatory bowel disease (see Chapter 69) which sites a 70% response rate if TPMT actually is less than average but only a 20 to 40% response and increased toxicity if TPMT levels are above average (Cuffari et al, 2004).

A chest radiograph should also be obtained to assess for the presence of a relatively uncommon side effect of hyper-sensitivity pneumonitis in patients with a chronic cough. See later section for maintenance therapy and discussion of elevating the doses for systematic reoccurrence.

Infliximab

The newest addition to our therapy options for patients with CD is antitumor necrosis factor therapy, infliximab (Sandborn and Targan, 2002). In patients with moderately to severely active CD, a single infusion of 5 mg/kg of inflix-imab (Remicade) results in response and remission rates of 81% and 48%, respectively, at 4 weeks (Hanauer et al, 2001). The efficacy does not appear to be influenced by the disease location. The onset of action is rapid, with response within 2 weeks of therapy and lasting approximately 8 to 12 weeks. An induction regimen with 3 infusions at weeks 0, 2, and 6 is recommended because of its superior efficacy and lower immunogenicity compared with single infusions (Hanauer et al, 2002). Most patients tolerate infliximab therapy well. Common side effects include headache, myalgia, upper respiratory tract infections, fatigue, nausea, abdominal pain, and diarrhea. Acute infusion reactions occur in approximately 6 to 16% of patients, and may present with flushing, palpitation, diaphoresis, chest pain, hypotension/hypertension, or dyspnea (Cheifetz et al, 2003). These acute reactions can usually be treated with slowing or stopping infusions, acetaminophen, antihistamine, steroids, and/or epinephrine. Delayed infusion reactions ("delayed hypersensitivity-like reactions") may develop 2 to 14 days after infusion, and are characterized by polyarthralgias, myalgias, fever, rash, and malaise. They are managed with acetaminophen, antihista-mines, and steroids. Although the development of antibodies against infliximab (ATF) is associated with a higher likelihood of infusion reactions, and a shorter duration response, routine determination of antibody presence is not yet recommended and many clinicians start AZA or MTX before going to infliximab. This lessens ATF formation. Cases of active tuberculosis in patients receiving infliximab have been reported. Thus, patients should be screened for latent or active tuberculosis before starting infliximab therapy. See later section on continuous versus episodic therapy.

Cyclosporine

Alternative immunomodulatory agents may be considered in patients refractory to above therapies. Intravenous (IV) cyclosporine A may be beneficial but it use is limited by the lack of sustained response following treatment cessation and potential toxicities associated with long term therapy (Sandborn, 1996). More importantly, the absorption of cyclopsorine A is dependent on the gut motility, bowel length, intact mucosa, and the presence of bile. All these factors are likely compromised in patients with SB CD.

Other Immunomodulators

Tacrolimus (FK 506) has similar actions as cyclosporine. It is an alternative to cyclosporine because its bioavailability is less dependent on intact bowel mucosa and bile flow. It may be considered in patients with complicated proximal SB CD. Mycophenolate mofetil (CellCept) has similar properties as AZA or 6-MP, and is used primarily as an alternative immunosuppressive agent for patients with perianal disease who cannot tolerate or have failed the latter. Mycophenolate may have a faster onset of action but shorter duration than AZA or 6-MP.

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